Over the past decade, investigators have come to recognize the importance of the extracellular matrix (ECM) in directing the growth, differentiation and function of the overlying epithelium. Getzenberg et al., xe2x80x9cThe Tissue Matrix: Cell Dynamics and Hormone Actionxe2x80x9d, Endocrine Rev., 11:399-417 (1990). The interaction between cell and extracellular matrix (or substratum) is mediated by several classes of cell adhesion molecules, one of the most important being the integrins. Albelda et al., xe2x80x9cIntegrins and Other Cell Adhesion Moleculesxe2x80x9d, FESEB J., 4:2868-2880 (1990). Buck et al., xe2x80x9cIntegrin, a Transmembrane Glycoprotein Complex Mediating Cell-Substratum Adhesionxe2x80x9d, J. Cell Sci. Suppl., 8:231-250 (1987). This diverse family of glycoprotein receptors is expressed on the cell membrane as heterodimeric xcex1 and xcex2 subunits and is involved in both cell-cell and cell-substratum adhesion. Specific recognition and binding of extracellular matrix (ECM) components such as fibronectin (FN), laminin (LM) and collagen (Col) transmit information to the cytoskeletal structure, an interaction which may have major roles in promoting hormone responsiveness and genomic activation. Burridge et al., xe2x80x9cFocal Adhesions: Transmembrane Junctions Between the Extracellular Matrix and the Cytoskeletonxe2x80x9d, Ann. Rev. Cell. Biol. 4: 487-525 (1988) and Getzenberg et al. supra.
Although extensive information exists about specific integrin proteins, for example, Hemler, M. E. xe2x80x9cVLA Proteins in the Integrin Family: Structures, Functions and Their Role on Leukocytesxe2x80x9d, Annu. Rev. Immunol: 365-400 (1990), little is known concerning the distribution of these receptors in the female reproductive tract. In the uterus, the endometrium, composed of glandular epithelium and associated mesenchyme (stroma), maintains complex temporal and spatial functions in response to the cyclic hormonal milieu. The search for morphological or biochemical markers for uterine receptivity has been unsuccessful to date as reported by Rogers and Murphy, xe2x80x9cUterine Receptivity for Implantation: Human Studiesxe2x80x9d, in Blastocyst Implantation, Yoshinaga, K. ed., Serono Symposia, pp. 231-238 (1989). Once such markers are identified, their role in endometrial phenomena including embryo implantation, fertility, contraception and endometrial maturation and receptivity can likely also be identified. Thus, as some integrins appear to meet the criteria for markers of receptivity there is a great need for methods of detecting integrin cell adhesion molecules in endometrium.
The present invention is directed to methods of detecting receptivity of endometrium to embryo implantation by detecting the xcex23 subunit of the xcex1v/xcex23 integrin in endometrium with a monoclonal antibody.
Methods of diagnosing fertility and methods of monitoring endometrial maturation in a mammal are also provided by monitoring the appearance of the xcex23 subunit of integrin in endometrium from a plurality of stages of the endometrial cycle. This is preferably done with a monoclonal antibody.
The present invention also provides methods of detecting the optimal window of embryo implantation in the endometrium by detecting the xcex23 subunit of integrin in an endometrial sample, preferably with a monoclonal antibody.
Further aspects of the invention include methods of preventing embryo implantation by contacting the xcex23 subunit of integrin in the endometrium with neutralizing Fab antibody fragments to xcex23. Methods of in vitro fertilization are also embodiments of the invention. These comprise detecting the xcex23 subunit of integrin in an endometrial sample, fertilizing an egg in vitro, and introducing the zygote into the uterus having endometrial tissue expressing the xcex23 subunit.
Contraceptive and diagnostic kits are also contemplated hereby.
These and other aspects of the invention will become more apparent from the following detailed description when taken in conjunction with the following figures.